Deazaflavin inhibitors of TDP2 with cellular activity can affect etoposide influx and/or efflux

Komulainen, Emilia, Pennicott, Lewis, Le Grand, Darren and Caldecott, Keith (2019) Deazaflavin inhibitors of TDP2 with cellular activity can affect etoposide influx and/or efflux. ACS Chemical Biology, 14 (6). pp. 1110-1114. ISSN 1554-8929

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Abstract

Tyrosyl DNA phosphodiesterase 2 (TDP2) facilitates the repair of topoisomerase II (TOP2)-linked DNA double-strand breaks and, as a consequence, is required for cellular resistance to TOP2 “poisons”. Recently, a deazaflavin series of compounds were identified as potent inhibitors of TDP2, in vitro. Here, however, we show that while some deazaflavins can induce cellular sensitivity to the TOP2 poison etoposide, they do so independently of TDP2 status. Consistent with this, both the cellular level of etoposide-induced TOP2 cleavage complexes and the intracellular concentration of etoposide was increased by incubation with deazaflavin, suggesting an impact of these compounds on etoposide uptake/efflux. In addition, deazaflavin failed to increase the level of TOP2 cleavage complexes or sensitivity induced by m-AMSA, which is a different class of TOP2 poison to which TDP2-defective cells are also sensitive. In conclusion, while deazaflavins are potent inhibitors of TDP2 in vitro, their limited cell permeability and likely interference with etoposide influx/efflux limits their utility in cells.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Research Centres and Groups: Sussex Drug Discovery Centre
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Lewis Pennicott
Date Deposited: 23 Sep 2019 09:41
Last Modified: 23 Sep 2019 09:50
URI: http://sro.sussex.ac.uk/id/eprint/86321

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